Pulvinar contributions to visual cortical processing in the rat

The extrageniculate visual pathway, which carries visual information from the retina through the superficial layers of the superior colliculus and the pulvinar nucleus, is poorly understood. Several studies have implicated this pathway, in particular the pulvinar, in cognitive tasks such as selective attention, but no specific mechanism or circuit has been described that could support such a function. In order to better understand what role this secondary visual pathway serves, here we examine the basic anatomical and functional properties of cells in the pulvinar, and what driving or modulating effect these cells have on visual cortex. In the first study, we made extracellular recordings in the pulvinar nucleus of lightly anesthetized rats. We identified visually responsive cells that have large receptive fields on the order of 80 degrees of visual field, fire selectively in response to low spatial frequencies, and can sometimes be selective to the direction or orientation of moving grating stimuli. We also determined that the anatomically-defined lateral subdivision encodes a greater diversity of temporal frequency stimuli than the more medial subdivision, which has better direction selectivity. In the second study, we used modified rabies viruses to retrogradely trace connections between rat pulvinar and visual cortex in order to better understand from where pulvinar receives its visual information and to which cortical areas it is best connected. We found a significantly weaker projection from pulvinar to primary visual cortex (V1) than from pulvinar to higher visual cortex (V2). In the final study, we designed and tested a new modified rabies virus to optically excite and silence populations of the more numerous projections to V2 from the rat pulvinar. We found that pulvinar modulates cortical size tuning and suppresses flash responses, but doesn’t drive activity in V2. This dissertation builds a foundational understanding of the role of the pulvinar nucleus in rodents, illustrating how pulvinar integrates spatiotemporal information from visual cortex and the superior colliculus, and regulates firing rates in rodent V2. The new rabies virus variant described here is well suited to test theories of pulvinar function, in addition to its wide potential applications in non-transgenic animals such as cats or non-human primates, where models of pulvinar are already well developed

T0901317 is a potent PXR ligand: Implications for the biology ascribed to LXR

AbstractThe liver X receptors (LXRα and β) are nuclear receptors that coordinate carbohydrate and lipid metabolism. Insight into the physiologic roles of the LXRs has been greatly facilitated by the discovery of potent synthetic agonists. Here we show that one of these compounds, T0901317, is also a high-affinity ligand for the xenobiotic receptor pregnane X receptor (PXR). T0901317 binds and activates PXR with the same nanomolar potency with which it stimulates LXR activity. T0901317 induces expression not only of LXR target genes, but also of PXR target genes in cells and animals, including the scavenger receptor CD36, a property not shared by more specific LXR ligands, such as GW3965. Activation of PXR targets may explain why T0901317 induces dramatic liver steatosis, while GW3965 has a milder effect. These results suggest that many of the biological activities heretofore associated with LXR activation may be mediated by PXR, not LXR. Since T0901317 has been widely used in animals to study LXR function, the in vivo effects of this compound ascribed to LXR activation should be re-examined

Moderating teen drinking: Combining social marketing and education

This paper outlines a pilot study that was undertaken in Australia in 2011 that combined social marketing with education. An intervention targeting 14-16 year olds to influence attitudes and behavioural intentions towards moderate drinking was developed and tested. Game On:Know alcohol (GO:KA) is a six-module intervention that is delivered to a year level cohort in an auditorium. GO:KA combines a series of online and offline experiential activities to engage (with) students. Following social marketing benchmark criteria, formative research and competitive analysis were undertaken to create, implement and evaluate an intervention. The intervention was delivered in one all boys' and one all girls' school in April and June 2011, respectively. A total of 223 Year 10 students participated in GO:KA with the majority completing both pre- and post-surveys. Paired samples t-tests and descriptive analysis were used to assess attitudinal and behavioural intention change. Attitudinal change was observed in both schools while behavioural intentions changed for girls and not boys according to paired samples t-testing. Post hoc testing indicated gender differences. The lack of a control group is a key limitation of the current research that can be overcome in the 20 school main study to be conducted in 2013-2015. The current study provides evidence to suggest that a combined social marketing and education intervention can change teenage attitudes towards moderate drinking whilst only changing behavioural intentions for female teenagers. Analysis of the intervention provides insight into gender differences and highlights the need for a segmented approach

Lightweight Integrated Solar Array (LISA): Providing Higher Power to Small Spacecraft

Affordable and convenient access to electrical power is essential for all spacecraft and is a critical design driver for the next generation of smallsats, including CubeSats, which are currently extremely power limited. The Lightweight Integrated Solar Array (LISA), a concept designed, prototyped, and tested at the NASA Marshall Space Flight Center (MSFC) in Huntsville, Alabama provides an affordable, lightweight, scalable, and easily manufactured approach for power generation in space. This flexible technology has many wide-ranging applications from serving small satellites to providing abundant power to large spacecraft in GEO and beyond. By using very thin, ultraflexible solar arrays adhered to an inflatable or deployable structure, a large area (and thus large amount of power) can be folded and packaged into a relatively small volume

SRSF2 Is Essential For Hematopoiesis and Its Mutations Dysregulate Alternative RNA Splicing In MDS

Abstract Myelodysplastic syndromes (MDS) are a group of neoplasms that are ineffective in generating multiple lineages of myeloid cells and have various risks to progress to acute myeloid leukemia. Recent genome-wide sequencing studies reveal that mutations in genes of splicing factors are commonly associated with MDS. However, the importance of these splicing factors in hematopoiesis has been unclear and the causal effect of their mutations on MDS development remains to be determined. One of these newly identified genes is SRSF2, and its mutations have been linked to poor survival among MDS patients. Interestingly, most of SRSF2 mutations occur at proline 95 and the majority of these mutations change this proline to histidine (P95H). Given that SRSF2 is a well-characterized splicing factor involved in both constitutive and regulated splicing, we hypothesize that SRSF2 plays an important role in normal hematopoiesis and the SRSF2 mutations induce specific changes in alternative splicing that favor disease progression. We first examined the role of SRSF2 in hematopoiesis by generating Srsf2 null mutation in mouse blood cells via crossing conditional Srsf2 knockout mice (Srsf2f/f) with blood cell-specific Cre transgenic mice (Vav-Cre). The mutant mice produced significantly fewer definitive blood cells (10% of wild type controls), exhibited increased apoptosis in the remaining blood cells, and died during embryonic development. Importantly, we detected no hematopoietic stem/progenitor cells (lineage-/cKit+) in E14 fetal livers of Vav-Cre/Srsf2f/f mice. These results indicate that SRSF2 is essential for hematopoiesis during embryonic development. We next examined the role of SRSF2 in adult hematopoiesis by injecting polyIC into mice that carry a polyIC inducible Cre expression unit. Unexpectedly, after multiple polyIC treatments, the Srsf2f/f mice stayed alive during several months of observation. Time course genotyping analyses of polyIC treated mice revealed an increased rate of incomplete Srsf2 deletion in peripheral blood cells. These observations suggest that Srsf2 ablation did not cause immediate cell lethality in differentiated blood cells, but the gene is indispensable for the function of blood stem/progenitor cells. Since mutations of splicing factors are generally heterozygous in MDS patients, we also examined mice with Srsf2+/- blood cells. No obvious defect of hematopoiesis was observed under normal conditions or in response to stress with 5-FU treatment and sublethal irradiation. To gain molecular insight into the splicing activity of MDS-associated mutant forms of SRSF2, we performed large-scale alternative splicing surveys by using RNA-mediated oligonucleotide annealing, selection, and ligation coupled with next-generation sequencing (RASL-seq) previously developed in our lab, which offers a robust and cost-effective platform for splicing profiling. Compared to vector transduction controls, we found that overexpression of both wild type and P95H SRSF2 induced many, but distinct changes in alternative splicing in lineage-negative bone marrow cells, and importantly, we noted several changes in genes with known roles in hematopoietic malignancies that were uniquely induced by the mutant SRSF2. To further link the mutations to altered splicing in MDS patients, we also applied RASL-seq to a large number of MDS patient samples with or without mutations in SRSF2 or other splicing regulators. The data revealed a specific set of alternative splicing events that are commonly linked to MDS with splicing factor mutations. These findings strongly suggest that many of these mutations in splicing regulators are gain-of-function mutations that are causal to MDS. In conclusion, we report that SRSF2 plays an essential role in hematopoietic stem/progenitor cells and that the MDS-associated mutations in SRSF2 have a dominant effect on RNA alternative splicing. These findings provide functional information and molecular basis of SRSF2 and its MDS-related mutations in hematopoiesis and related clinical disorders. Disclosures: No relevant conflicts of interest to declare

Lightweight Innovative Solar Array (LISA): Providing Higher Power to Small Spacecraft

Affordable and convenient access to electrical power is essential for all spacecraft and is a critical design driver for the next generation of smallsats, including cubesats, which are currently extremely power limited. The Lightweight Innovative Solar Array (LISA), a concept designed, prototyped, and tested at the NASA Marshall Space Flight Center (MSFC) in Huntsville, Alabama provides an affordable, lightweight, scalable, and easily manufactured approach for power generation in space. This flexible technology has many wideranging applications from serving small satellites to providing abundant power to large spacecraft in GEO and beyond. By using very thin, ultraflexible solar arrays adhered to an inflatable structure, a large area (and thus large amount of power) can be folded and packaged into a relatively small volume. The LISA array comprises a launchstowed, orbitdeployed structure on which lightweight photovoltaic devices and, potentially, transceiver elements are embedded. The system will provide a 2.5 to 5 fold increase in specific power generation (Watts/kilogram) coupled with a >2x enhancement of stowed volume (Watts/cubicmeter) and a decrease in cost (dollars/Watt) when compared to stateoftheart solar arrays

Modelling diffusive mixing in antisolvent crystallization

Diffusion controls local concentration profiles at interfaces between segregated fluid elements during mixing processes. This is important for antisolvent crystallization, where it is intuitively argued that local concentration profiles at interfaces between solution and antisolvent fluid elements can result in significant supersaturation overshoots over and above that at the final mixture composition, leading to poorly controlled nucleation. Previous work on modeling diffusive mixing in antisolvent crystallization has relied on Fickian diffusion, where concentration gradients are the driving force for diffusion. This predicts large overshoots in the supersaturation at interfaces between solution and antisolvent, as is often intuitively expected. However, chemical potential gradients provide a more physically realistic driving force for diffusion, and in highly nonideal solutions, such as those in antisolvent crystallization, this leads to nonintuitive behavior. In particular, as solute diffusion toward antisolvent is severely hindered, it can diffuse against its concentration gradient away from antisolvent. We apply thermodynamically consistent diffusion model based on the multicomponent Maxwell–Stefan formulation to examine diffusive mixing in a nonideal antisolvent crystallization system. Large supersaturation overshoots above that at the final mixture composition are not found when a thermodynamically consistent approach is used, demonstrating that these overshoots are modeling artifacts and are not expected to be present in physical systems. In addition, for certain conditions, localized liquid–liquid spinodal demixing is predicted to occur during the diffusive mixing process, even when the final mixture composition is outside the liquid–liquid phase separation region. Intermittent spinodal demixing driven by diffusive mixing may provide a novel explanation for differences of nucleation behaviors among various antisolvents

WIMPonium and Boost Factors for Indirect Dark Matter Detection

We argue that WIMP dark matter can annihilate via long-lived "WIMPonium" bound states in reasonable particle physics models of dark matter (DM). WIMPonium bound states can occur at or near threshold leading to substantial enhancements in the DM annihilation rate, closely related to the Sommerfeld effect. Large "boost factor" amplifications in the annihilation rate can thus occur without large density enhancements, possibly preferring colder less dense objects such as dwarf galaxies as locations for indirect DM searches. The radiative capture to and transitions among the WIMPonium states generically lead to a rich energy spectrum of annihilation products, with many distinct lines possible in the case of 2-body decays to $\gamma\gamma$ or $\gamma Z$ final states. The existence of multiple radiative capture modes further enhances the total annihilation rate, and the detection of the lines would give direct over-determined information on the nature and self-interactions of the DM particles.Comment: 8 pages, PDFLaTex, 5 figures, references added, published version